Twist1 in Human White Adipose Tissue and Obesity

Pettersson, Amanda; Mejhert, Niklas; Jernås, Margareta; Carlsson, Lena; Dahlman, Ingrid; Laurencikiene, Jurga; Arner, Peter; Rydén, Mikael

doi:10.1210/jc.2010-0929

Cited by 41 publications

(55 citation statements)

References 32 publications

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“…mRNA and protein expression of Twist1 in human AT are lower in obese than non-obese individuals [15]. Moreover, it has been reported that low mRNA and protein expression of Twist1 is associated with increased expression of proinflammatory cytokines and decreased insulin sensitivity in humans [15]. In accordance with the latter study in human AT, we found gene expression of Twist1 to be significantly lower in the obese than the non-obese group.…”

Section: Discussionsupporting

confidence: 89%

“…In humans, Twist1 is expressed mainly in adipocytes of AT, but not in the liver, pancreas or skeletal muscle [31]. mRNA and protein expression of Twist1 in human AT are lower in obese than non-obese individuals [15]. Moreover, it has been reported that low mRNA and protein expression of Twist1 is associated with increased expression of proinflammatory cytokines and decreased insulin sensitivity in humans [15].…”

Section: Discussionmentioning

confidence: 99%

“…AT inflammation is characterised by macrophage infiltration and increased levels of proinflammatory chemokines, such as monocyte chemoattractant protein-1 (MCP-1), and macrophage markers, such as cluster of differentiation 68 (CD68) [9][10][11][12]. Levels of anti-inflammatory markers such as Twist-related protein 1 (Twist1) and adiponectin are significantly lower in obese insulin-resistant than in nonobese insulin-sensitive people [13][14][15]. These changes have been suggested to be causally linked to hepatic steatosis and insulin resistance [16].…”

Section: Introductionmentioning

confidence: 99%

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Adipose tissue is inflamed in NAFLD due to obesity but not in NAFLD due to genetic variation in PNPLA3

et al. 2013

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Aims/hypothesis The rs738409 C>G single-nucleotide polymorphism in PNPLA3 leads to a missense mutation (I148M) which increases liver fat but does not cause insulin resistance. We hypothesised that patients with non-alcoholic fatty liver disease (NAFLD) due to the PNPLA3 variant ('PNPLA3 NAFLD'=PNPLA3-148MM) do not have adipose tissue (AT) inflammation in contrast with those with NAFLD due to obesity ('obese NAFLD'). Methods Biopsy specimens of AT were taken, and PNPLA3 genotype and liver fat ( 1 H-magnetic resonance spectroscopy) were determined in 82 volunteers, who were divided into groups based on either median BMI (obese 36.2± 0.7 kg/m 2 ; non-obese 26.0±0.4 kg/m 2 ) or PNPLA3 genotype. All groups were similar with respect to age and sex.The PNPLA3 subgroups were equally obese (PNPLA3-148MM, 31.1 ± 1.3 kg/m 2 ; PNPLA3-148II, 31.2 ± 0.8 kg/m 2 ), while the obese and non-obese subgroups had similar PNPLA3 genotype distribution. Gene expression of proinflammatory (MCP-1, CD68) and anti-inflammatory (Twist1, ADIPOQ) markers was measured using quantitative real-time RT-PCR. Results Liver fat was similarly increased in obese NAFLD (9.5±1.3% vs 5.1±0.9%, obese vs non-obese, p=0.007) and PNPLA3 NAFLD (11.4± 1.7% vs 5.3± 0.8%, PNPLA3-148MM vs PNPLA3-148II, p<0.001). Fasting serum insulin was higher in the obese than the non-obese group (76±6 vs 47±6 pmol/l, p<0.001), but similar in PNPLA3-148MM and PNPLA3-148II (60±8 vs 62±5 pmol/l, NS). In obese vs non-obese, MCP-1 and CD68 mRNAs were upregulated, whereas those of Twist1 and ADIPOQ were significantly downregulated. AT gene expression of MCP-1, CD68, Twist1 and ADIPOQ was similar in PNPLA3-148MM and PNPLA3-148II groups. Conclusions/interpretation PNPLA3 NAFLD is characterised by an increase in liver fat but no insulin resistance or AT inflammation, while obese NAFLD has all three of these features. Keywords

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Adipose tissue is inflamed in NAFLD due to obesity but not in NAFLD due to genetic variation in PNPLA3

et al. 2013

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“…TNF-α release from abdominal subcutaneous WAT (scWAT) was determined as described [23]. In short, WAT explants were incubated for 2 h after which TNF-α secretion into medium was quantified with ELISA (R&D Systems, Minneapolis, MN, USA) as ng per 10 7 adipocytes.…”

Section: Methodsmentioning

confidence: 99%

MAFB as a novel regulator of human adipose tissue inflammation

et al. 2015

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Aims/hypothesis Dysregulated expression of metabolic and inflammatory genes is a prominent consequence of obesity causing insulin resistance and type 2 diabetes. Finding causative factors is essential to understanding progression of these pathologies and discovering new therapeutic targets. The transcription factor V-maf musculoaponeurotic fibrosarcoma oncogene homologue B (MAFB) is highly expressed in human white adipose tissue (WAT). However, its role in the regulation of WAT function is elusive. We aimed to characterise MAFB expression and function in human WAT in the context of obesity and insulin resistance. Methods MAFB mRNA expression was evaluated in human WAT from seven cohorts with large inter-individual variation in BMI and metabolic features. Insulin-induced adipocyte lipogenesis and lipolysis were measured and correlated with MAFB expression. MAFB regulation during adipogenesis and the effects of MAFB suppression in human adipocytes was investigated. MAFB regulation by TNF-α was examined in human primary adipocytes and THP-1 monocytes/ macrophages. Results MAFB expression in human adipocytes is upregulated during adipogenesis, increases with BMI in WAT, correlates with adverse metabolic features and is decreased after weight loss. MAFB downregulation decreases proinflammatory gene expression in adipocytes and interferes with TNF-α effects. Interestingly, MAFB is differentially regulated by TNF-α in adipocytes (suppressed) and THP-1 cells (upregulated). Further, MAFB is primarily expressed in WAT macrophages/ monocytes and its expression correlates with macrophage and inflammatory markers. Conclusions/interpretation Our findings indicate that MAFB is a regulator and a marker of adipose tissue inflammation, a process that subsequently causes insulin resistance.

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“…TWIST1 expression in Thelper 1 (T H 1) lymphocytes and bone marrow-derived macrophages attenuates the expression of IFN-g, interleukin (IL)-2, and TNF-a, further implicating TWIST1 in the regulation of cytokine expression (25)(26)(27). It was also reported that CCL2 expression may be subject to regulation by TWIST1 (28). The relationship between androgens and these EMT-related proteins as well as the relation between TWIST1 and CCL2 in prostate cells remains unresolved.…”

Section: Introductionmentioning

confidence: 99%

Indole-3-Carbinol and 3′,3′-Diindolylmethane Modulate Androgen's Effect on C-C Chemokine Ligand 2 and Monocyte Attraction to Prostate Cancer Cells

Kim

Milner

et al. 2013

Cancer Prevention Research

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Inflammation has a role in prostate tumorigenesis. Recruitment of inflammatory monocytes to the tumor site is mediated by C-C chemokine ligand 2 (CCL2) through binding to its receptor CCR2. We hypothesized that androgen could modulate CCL2 expression in hormone-responsive prostate cancer cells and thereby promote recruitment of monocytes. Given the inhibitory effect of broccoli-derived compounds indole-3-carbinol (I3C) and 3,3 0 -diindolylmethane (DIM) on androgen-dependent pathways, we also reasoned that I3C and DIM could modulate the effect of androgen on CCL2-mediated pathways. Dihydrotestosterone was found to induce a time-dependent (0-72 hours) and concentration-dependent (0-1 nmol/L) increase in CCL2 mRNA levels in androgen-responsive human prostate cancer cells (LNCaP). This increase in CCL2 mRNA corresponded with increased secretion of CCL2 protein. The effect of dihydrotestosterone was mediated through an androgen receptor (AR)-dependent pathway as small inhibitor RNA against AR negated the induction of CCL2. Although dihydrotestosterone also induced TWIST1 mRNA, an epithelialmesenchymal transition-related factor, and purported inducer of CCL2, blocking its expression with small inhibitor RNA did not inhibit dihydrotestosterone induction of CCL2 mRNA. Moreover, conditioned media from androgen-treated cells promoted human monocyte THP-1 cell migration and this effect was blocked by antibody against CCL-2. Both I3C and DIM inhibited promotional effects of dihydrotestosterone on CCL2 and migration. These results show that androgen may regulate CCL2 and promote inflammatory microenvironment in prostate tumors and that this process can be blocked by broccoli-derived compounds.Cancer Prev Res; 6(6); 519-29. Ó2013 AACR.

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Twist1 in Human White Adipose Tissue and Obesity

Abstract: Low twist1 expression in human WAT correlates with obesity and an insulin-resistant phenotype, which may be mediated by an increased sensitivity to the proinflammatory effect of TNFα.

Cited by 41 publications

References 32 publications

Adipose tissue is inflamed in NAFLD due to obesity but not in NAFLD due to genetic variation in PNPLA3

Adipose tissue is inflamed in NAFLD due to obesity but not in NAFLD due to genetic variation in PNPLA3

MAFB as a novel regulator of human adipose tissue inflammation

Indole-3-Carbinol and 3′,3′-Diindolylmethane Modulate Androgen's Effect on C-C Chemokine Ligand 2 and Monocyte Attraction to Prostate Cancer Cells

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